Matrix metalloproteinase 2 (MMP-2) activation has been described as a "mast
er switch" which triggers tumor spread and metastatic progression. We show
here that type IV collagen, a major component of basement, membranes, promo
tes MMP-2 activation by HT1080 cells. When plated on plastic, HT1080 cells
constitutively processed the 66-kDa pro-MMP-2 into a 62-kDa intermediate ac
tivated form, most probably through a membrane type (MT) 1 MMP-dependent me
chanism. In the presence of type IV collagen, part of this intermediate for
m was further processed to fully activated 59-kDa MMP-2. This activation wa
s prevented by tissue inhibitor of MMP (TIMP)-2 and a broad-spectrum hydrox
amic acid-based synthetic MMP inhibitor (GIP129471). Type IV collagen-media
ted pro-MMP-2 activation did not involve either a transcriptional modulatio
n of MMP-2, MT1-MMP, or TIMP-2 expression nor any alteration of MT1-MMP pro
tein synthesis or processing. An inverse relationship between MMP-2 activat
ion and the concentration of secreted TIMP-2 was observed. This is consiste
nt with our previous report that TIMP-2 degradation is probably linked to t
he MT1-MMP-dependent MMP-2 activation mechanism. Because invasive tumor cel
ls must breach basement membranes at different steps of the metastatic diss
emination, the ability of HT1080 cells to activate pro-MMP-2 in the presenc
e of type IV collagen might represent a key regulatory mechanism for the ac
quisition of an invasive potential. (C) 2000 Academic Press.